Tropyl 7-azaindol-3-ylcarboxyamides as antitussive agent

ABSTRACT

Tropyl 7-azaindol-3-ylcarboxamides of the formula ##STR1## or their N-oxides of the formula ##STR2## wherein R is hydrogen, alkyl, cyclo-alkyl, arylalkyl or acyl, are particularly effective as antitussive agents.

This is a 3H application of PCT/IB 94/00234 filed on Aug. 4, 1994.

The present invention refers to tropyl 7-azaindol-3-ylcarboxyamides offormula (I) ##STR3## wherein the symbol indicates that compounds (I) mayhave the configuration exo(or β-) or endo(or α-) and

R represents a hydrogen atom; a saturated linear or branched C₁ -C₄alkyl; a C₇ -C₉ arylalkyl; a --(CH₂)_(n) --(C₃ -C₇) cycloalkyl groupwherein n is an number between 0 and 4; a C₁ -C₁₂ acyl group,

s repreents 0 or 1.

As C₃ -C₇ membered cycloaliphatic ring cyclopropyl, cyclopentyl andcyclohexyl are preferred.

As C₇ -C₉ arylalkyl the benzyl and the phenethyl radical are preferred.

As --(CH₂)n---(C₃ -C₇) cycloalkyl group, the cyclopropylmethyl group ispreferred.

As C₁ -C₁₂ acyl group the formyl group is preferred.

Among C₁ -C₄ alkyl radicals are preferred the methyl, ethyl andisopropyl radicals.

A further object of the invention is represented by the compounds offormula (I) wherein the aminotropyl group is protected by a suitableconventional protecting group among which is preferred theter-butoxycarbonyl. Also included in the scope of the invention are theacid addition salts of the compounds (I) with suitable, non-toxic,pharmaceutically acceptable acids. Among these salts are cited thehydrochorides, hydrobromides, alkyl and arylsulfonates, succinates,tartrates and citrates.

The compounds of formula (I) are obtained by reaction of a tropylamineof formula (III): ##STR4## wherein the symbols R and have the abovedefined meaning, with an optionally activated azaindolyl-3-carboxylicacid (IV): ##STR5## wherein the symbol s, has the above mentionedmeaning and T represents a hydroxy group or the residue of a carboxylicacid activating group. Preferred activating groups are those well knownin the art such as, for example, chorine, bromine, azide, imidazolide,p-nitrophenoxy, 1-benzotriazole, N--O-succinimide, acyloxy and morespecifically, pivaloyloxy, C1-C4 alkoxycarbonyloxy, such as, forexample, C₂ H₅ OCO--O--, a dialkyl- or a dicycloalkyl-O-ureide. Thecarboxyamides of formula (I) are isolated from the reaction mixture asfree bases or as addition compounds with a suitable mineral or organicacid. When the compounds of formula (IV) are used in their free acidform, the reaction is carried out in the presence of a condensing agentsuch as, for example, a carbodiimide, optionally in the presence of anactivating agent such as, for example, hydroxybenzotriazole orhydroxysuccinimide, with the intermediate formation of dialkyl- ordicycloalkyl-O-ureides. Typical condensing agents are the dicyclohexyl-and the diisopropylcarbodiimide, carbodiimides soluble in an aqueousmedium etc. Preferred reaction conditions are those which provide theuse of equimolar amounts of the reagents, in inert solvents such asethyl acetate, aromatic hydrocarbons such as benzene and toluene,cycloalkanes such as cyclohexane, dioxane, tetrahydrofuran,dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone, acetonitrileand the mixtures thereof, operating at a temperature between roomtemperature and the reflux temperature of the mixture, preferably at50°-60° C.

The bicyclic tropylamines (III) are generally well known and alsocommercially available compounds. They may be prepared using methodsknown in the art; see for example, the method for the preparation of3α-tropylamine of S. Archer et al., J. Amer. Chem. Soc., 79, 4194, 1957and the method described for the preparation of 3β-tropylamine R.Willstatter et al., Chem. Ber., 31, 1201, 1898, S. Archer et al., J.Amer. Chem. Soc., 80, 4677, 1858, and also A. Stoll et al., Helv. Chim.Acta 38, 559, 1955; further preparations of said tropylamines aredescribed by P. Dostert et al., FR 2.449.570 (13 Aug. 1982) C.A. 98,126444q (1983); P. Donatsch et al., DE 33 22754 (29 Dec. 1983); M.Langlois et al., FR 2.548.666 (11 Jan. 1985) C.A. 103, 123757e (1985);E. A. Watts PCT WO 85 00.170 (17 Jan. 1985) C.A. 103 123376e (1985); D.Lednicer et al., EP 147.044 (3 Jul. 1985) C.A. 104 1949 1986.

The preparation of the 1H-pyrrole|2,3-b|pyridine-3-carboxylic acid7-oxide, as well as a general procedure for the preparation of1H-pyrrole|2,3-b|pyridine 7-oxide, has been described by S. W. Schnelleret al., (J. Org. Chem., 45, 4045, 1980).

The preparation of the 1H-pyrrole|2,3-b| pyridine-3-carboxylic acid aswell as the ethyl ester thereof have been described by M. M. and B. L.Robinson on J. Amer. Chem. Soc., 78, 1247, 1956. In general,7-azaindoles and their homologues 1- or 2-substituted or 1- or2-disubstituted, for the preparation of which see for example, R. R.Lorenz et al., J. Org. Chem., 30, 2531, 1965 and references citedtherein, may be converted by a Mannich reaction into their corresponding3-dialkylaminomethyl derivatives and then transformed in thecorresponding 3-formyl-7-azaindoles which, substantially according tothe above mentioned procedure of M. M. and B. L. Robinson, are convertedinto their corresponding esters and carboxilic acids.

More particularly it has been found that, in a halogenated solvent andin the presence of a suitable catalyst such as aluminum chloride, i.e.in Friedel-Krafts conditions, the 7-azaindoles themselves react with atrihaloacetylhalides, preferably tricloacetylchloride, to give, with ayield almost quantitative, the corresponding3-trihaloacetyl-7-azaindoles such as, for example,3-trichloroacetyl-1H-pyrrole 2,3-b!pyridine which, with furthertreatment with bases, such as potassium hydroxide, undergo thehaloformic transposition into the corresponding7-azaindolyl-3-carboxylic acids.

The following Examples are given by way of better illustrating theinvention without limiting it.

EXAMPLE 1 N-(endo-8-methyl-8-azabicyclo3.2.1!oct-3-yl)-7-azaindolyl-3-carboxamide (Compound A)

In an inert gas atmosphere and under stirring, a solution of 5.4 ml oftrichloroacetyl chloride in 27 ml dichloromethane is added in the courseof 10 minutes to a suspension of 6.8 g aluminum chloride in 54 mldichloromethane cooled to -78° C. It is maintained at this temperaturefor 15 minutes then warmed up to -40° C., maintaining under stirring fora further 45 minutes. A solution of 2 g 7-azaindole in 10 mldichloromethane is then added, stirred for 15 minutes at -40° C. and thetemperature is allowed to rise to 0° C. and stirring continued for afurther hour. Milliliters 26 of an aqueous solution of 1H hydrochloricacid are added carefully maintaining the temperature between 0° and 15°C.; after decomposition of the reagents, the phases are separated andthe organic phase is washed with water and treated under strong stirringwith sodium bicarbonate heptahydrate to obtain a white crystalline solidwhich is filtered and it gives 2.6 g 3-trichloroacetyl-1H-pyrrole-2,3-b!pyridine melting at 260° C. (with decomposition). The so obtainedcompound is suspended in 15 ml of a 10% potassium hydroxide aqueoussolution and the suspension is kept under strong stirring until completedissolution. By acidification of the solution to pH 3-4 with a 37%hydrochloric acid aqueous solution, 1.5 g 7-azaindolyl-3-carboxylic acidseparate by precipitation, melting point 230°-240° C. (withdecomposition).

To a solution of 1.5 g 7-azaindolyl-3-carboxylic acid in 24 ml of amixture 1:1 of tetrahydrofuran:dimethylformamide, 1.29 gendo-8-methyl-8-aza-bicyclo 3.2.1!oct-3-ylamine and 2.1 gdicyclohexylcarbodiimide are added.

The mixture is heated for 3 hours at 50° C., then it is evaporated tosmall volume, acidified with 2N hydrochloric acid and filtered removingthe dicyclohexylurea precipitate. The filtrate is saturated with sodiumchloride and after being made alkaline to pH 11 with sodium hydroxide,it is extracted with chloroform and it gives, by evaporation of thesolvent and crystallization of the residue from ethyl ether, 1.24 gN-(endo-8-methyl-8-azabicyclo 3.2.1!oct-3-yl)-7-azaindolyl-3-carboxamidemelting at 273° C. (Compound A). Operation is carried out according tothe previously described procedure and using instead ofendo-8-methyl-8-azabicyclo 3.2.1!oct-3-ylamine, 1-azabicyclo2.2.2!oct-3-yl-amine, N-(1-azabicyclo2.2.2!oct-3-yl)-7-azaindolyl-3-carboxamide melting at 275°-280° C. isobtained (Compound B).

EXAMPLE 2N-(8-methyl-8-azabicyclo|3.2.1|oct-3α-yl)-7-azaindolyl-3-carboxamide7-oxide.

To a solution of 1.5 g 7-azaindolyl-3-carboxilic acid 7-oxide in 30 mlacetonitrile, 2 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride are added in portions.

After 15 minutes of stirring, a solution of 1.29 g 3α-tropylamine in 10ml of acetonitrile is added. It is kept at room temperature for 2 hours,heated to 50° C. for 2 hours, concentrated under vacuo to a third of itsvolume and diluted with 100 ml of water. After several extractions withethyl acetate, the organic phases are collected together and evaporatedto dryness. The residue is purified by chromatography over silica gel(CHCl₃ :MeOH) to give 1.12 g N-(8-methyl-8-azabicyclo3.2.1!oct-3α-yl)-7-azaindolyl-3-carboxamide 7-oxide.

EXAMPLE 3 N-(8-cyclopropylmethyl-8-aza-bicyclo3.2.1!oct-3β-yl)-7-azaindolyl-3-carboxamide.

A solution of 2.9 g N-hydroxysuccinimide in 10 ml tetrahydrofuran isadded to a solution of 1.84 g 7-azaindolyl-3-carboxylic acid in 30 ml ofa 1:1 tetrahydrofuran and dimethylformamide mixture cooled to 0° C. andunder stirring. A solution of 2.1 ml morpholynethylisonitrile in 10tetrahydrofuran ml is dripped therein and stirring is maintained for afurther two hours to room temperature. It is diluted with 5 volumes ofwater, tetrahydrofuran is removed by evaporation under vacuum, it isacidified to pH 3-4 with a potassium acid sulphate aqueous solution andextracted with ethyl acetate. From the collected together organicextracts, by evaporation of the solvent, 2.6 g 7-azaindolyl-3-carboxylicacid succinimide ester crystallizes.

Grams 1.02 of the so obtained succinimide ester are dissolved at roomtemperature and in argon atmosphere in 7.5 ml acetonitrile and to thesolution 5 ml of a solution of 0.75 g3β-amino-8-cyclopropylmethyl-8-azabicyclo 3.2.1!octane in 0.5 mlacetonitrile are added. After 8 hours, the mixture is concentrated undervacuum to small volume and diluted with a sodium bicarbonate saturatedsolution until a slight alkaline pH. It is extracted four times with 20ml each of ethyl acetate and from the collected together extracts, afterevaporation of the solvent and crystallization from ethyl ether, 1.5 gof N-(8-cyclopropylmethyl-9-aza-bicyclo3.2.1!oct-38yl)-7-aza-indolyl-3-carboxiamide are obtained.

In a similar manner by reaction with the suitable 3-amino-8-azabicyclo3.2.1! octane are obtained:

N-(8-cyclopropylmethyl-8-azabicyclo3.2.1!oct-3α-yl-7-azaindolyl-3-carboxyamide;

N-(8-formyl-8-azabicyclo 3.2.1!oct-3α-yl)-7-azaindolyl-3-carboxyamide;

N-(8-tert-butoxycarbonyl-8-azabicyclo3.2.1!oct-3α-yl)-7-azaindolyl-3-carboxyamide;

N-(8-phenylethyl-8-azabicyclo3.2.1!oct-3α-yl)-7-azaindolyl-3-carboxyamide;

N-(8-benzyl-8-azabicyclo 3.2.1!oct-3α-yl)-7-azaindolyl-3-carboxyamide;

N-(8-cyclohexylmethyl-8-azabicyclo3.2.1!oct-3α-yl)-7-azaindolyl-3-carboxyamide;

N-(8-cyclopentylmethyl-8-azabicyclo3.2.1!oct-3α-yl)-7-azaindolyl-3-carboxyamide;

N-(8-ethyl-8-azabicyclo 3.2.1!oct-3α-yl)-7-azaindolyl-3carboxyamide;

N-(8-isopropyl-8-azabicyclo3.2.1!oct-3α-yl)-7-azaindolyl-3-carboxyamide.

EXAMPLE 4 N-(8-azabicyclo 3.2.1!oct-3α-yl)-7-azaindolyl-3-carboxyamidetri-fluoroacetate.

A solution of 0.3 g N-(8-tert-butoxycarbonyl-8-azabicyclo 3.2.1!oct-3α-yl-7-azaindolyl-3-carboxyamide in 2 ml of dichloromethane and 2ml of trifluoroacetic acid is maintained for 8hours at room temperaturethen the reaction mixture is evaporated to dryness under vacuum and theresidue, crystallized from ethyl ether:hexane, and it gives thetrifluoro acetate of N-(8-azabicyclo3.2.1!oct-3α-yl)-7-azaindolyl-3-carboxyamide.

Benzoyl N-quinuclidinylamides and N-tropylamides and analogous amides ofaryl- and heteroarylcarboxylic acids represent compounds which in thelast decade were the object of wide researches having as aim theidentification and the functional characterization of the subtypes ofthe serotonin (5-HT) receptor and the realization of ligands having highbond affinity and high receptor specificity. Substances belonging to thesame family of compounds have resulted clinically effective in thecontrol of the emesys induced by antitumoral chemotherapy, apharmacological event which was suppose to be modulated by 5-HT₃receptors in the area postrema. Lastly there are pharmacologicalindications which make believe that these substances because they are5-HT₃ antagonists, may be useful in correcting affections of the centralnervous system, such as, for example, schizophrenia, anxiety or the lossof memory, since 5-HT₃ receptors also seem to modulate the cholinergicneurons.

Specific examples of 5-HT₃ antagonists are, for example, Ondasetron, BRL24682 or N-(endo-8-methyl-8-azabicyclo-3.2.1!oct-3-yl)-2-methoxy-4-amino-5-chlorobenzamide, ICS-205-930 or(endo-8-methyl-8-azabicyclo 3.2.1!oct-3-yl)indolyl-3-carboxylate.

More recently, both quinuclidyl- and tropyl-amides of the 7-methyl-8-azaindolyl-3-carboxylic acid (T. Higashino et al., Toyo Jozo Co., EP483 836 (06 May 1992), C.A. 117 171436K and 2-methylimidazol|1,2-a|pyridin-3-carboxylic acid (K. Nitta et al., Mitsubishi Kasei Corp. JP01258679 (16 Oct. 1989), C.A. 112 178986v) have been described as 5-HT₃antagonists and therefore are useful as antiemetic, in the prevention ofnausea by cis-Platin and, more in general, as antiserotoninergic drugsto be used for the treatment of the migraine and anxiety.

The amides of the 7-azaindol-3-carboxylic acid (F. D. King, BeechamGroup, EP 254 584 (27 Jan. 1988) C.A. 109 93018u) have also beendescribed as 5-HT₃ -antagonists. Lastly, more recently, M. Kato et al.(Fujisawa Pharmac., JP 04021681 (24 Jan. 1991) C.A. 116 255499a)describe pyrrolpyridinecarboxyamides of azabicycloalkylamines as typical5-HT₃ antagonists with particular mention to the amides of3-amino-8-methylazabicyclo 3.2.1!octane with 1-methyl and1-ethyl-7-azaindolyl-3-carboxylic acids.

Compounds A and Compounds B of the present invention, which are examplesof endo-tropyl and quinuclidylamide of 7-azaindolyl-3-carboxylic acidrespectively have been studied "in vitro" for their interaction with the5-HT₁, 5-HT₂ and 5-HT₃ receptors.

                  TABLE I                                                         ______________________________________                                        Binding Test: 5-HT.sub.1  5-HT.sub.2                                                                            5-HT.sub.3                                  ______________________________________                                        % of inhibition at 3.6 10.sup.-5 M                                                                      IC.sub.50 M                                         Ondasetron    7.6         21.7    3 10.sup.-9                                 Compound A    0.0         8.6     3 10.sup.-6                                 (7-azaindolylcarboxy                                                          tropylamide)                                                                  Compound B    37.0        3.9     3 10.sup.-7                                 (7-azaindolylcarboxy                                                          quinuclidylamide)                                                             ______________________________________                                    

From the above study a first indication of an atypic behaviour of7-azaindolyl-3-carboxylic acid tropylamides when compared to thecorresponding quinuclidylamid surprisingly appeared.

The interaction of Compounds A and B with other receptors (α₁, α₂,benzodiazepine (o bzd), GABA A, δ) in comparison to the typical 5-HT₃antagonist Ondastron and BRL 24682 has been studied and for each casethe displacement % of the single selective ligand from the correspondingreceptor at concentration 10⁻⁵ M of the compounds under examination, hasbeen evaluated.

                  TABLE II                                                        ______________________________________                                                 Dispacement percentage                                               Receptors: α.sub.1                                                                          α.sub.2                                                                       bdz     Gaba A                                                                              σ                               ______________________________________                                        Ondasetron 72       30    *       38    45                                    BRL 24682  28       16    98      89     0                                    Compound A 13       *     *       83    70                                    Compound B  7       *     *       6.7   26                                    ______________________________________                                         *not active: no capacity of displacement of the ligand at a                   conc. 10.sup.-S M.                                                       

The disparity in behaviour between 7-azaindolyl-3-carboxylic acidquinuclidyl- and tropyl-amides results even more evident from theabove-listed data. 7-Azaindolylcarboxamide (Compound A) shows a veryweak interaction with 5-HT₃ receptors: 1,000 times lower than that ofOndasetron, which is a typical 5-HT₃ antagonist, and logarithmicallylower than that of Compound B.

Compound A itself shows surprisingly an unusual ability of a doubleinteraction, apparently selective, towards GABA A and δ receptors, whichability is definitely weak or absent in the correspondingquinuclidylamide and, to the contrary, it seems aspecific in 5-HT₃antagonist Ondasetron.

As to the other 5-HT₃ antagonist, BRL 24682, it is evident its highinteraction with the benzodiazepine and GABA A receptors, and itscomplete lacking of interaction with the receptors, thus allowing toexclude that the selective interaction of 7-azaindolylcarboxytropylamide(Compound A) with GABA A and δ receptors be a characteristic generallypresent in potential 5-HT₃ antagonists, or, at least in substances sodefined on the bases of a simple chemical structure analogy.

Besides these differences "in vitro" on the receptor behaviour greatdifferences has been evidenced "in vivo" in the tussive stimulusinhibition provoked by inhalation of irritant citric acid as well ascapsaicine aqueous solutions.

The compounds have been tested in guinea pigs in comparison to codeine,used as standard compound, at the single dose of 100 mg/kg according tothe technique of Charlier et al., (Arch. Int. Pharmacodyn., 134, 306,1961) which has been slightly modified.

The percent reduction evaluated in the number of short coughs afteradministration of the compound under examination taken in comparison tothe number of short coughs observed in each of the animals to which thecompound was administered, have been noted.

For each of the compounds under examination it has been also tested theeffect on the increase of the sleeping time induced by barbiturates. Thetest was carried out on mice by oral administration of a single dose of100 mg/kg of the compound.

The data obtained are listed in the following Table III.

                  TABLE III                                                       ______________________________________                                        % INHIBITION                                                                  of the coughing stimulus by:                                                                               sleeping time                                              ac. citric                                                                              capsaicin                                                                              increase                                         ______________________________________                                        Ondasetron  30.5        50.5     -8*                                          BRL 24682   44.1        n.d.     +34.8                                        Compound A  61.7        76.30    -28.9                                        (7-azaindolylcarboxy                                                          tropylamide)                                                                  Compound B  46.0        21.0     -7                                           (7-azaindolylcarboxy                                                          quinuclidylamide)                                                             Codeine     63.2        58.4     +106.4                                       ______________________________________                                         *at the dose of 10 mg/kg   n.d.: not determinable                        

In a successive study, carried out at different doses, using ascomparison compounds typical antitussive compounds commonly used intherapy, either having a central effect, i.e. codeine, or having aperipheral effect, i.e. levodropropizine, it has been observed that theprotecting antitussive effect of 7-azaindolylcarboxytropylamine(Compound A) depends on the dose administered. For these compounds aswell as for the most interesting reference compounds the dose inhibiting50% of the short coughs (ID₅₀) induced either by citric acid orcapsaicine has been determined.

                  TABLE IV                                                        ______________________________________                                        ID.sub.50 in mg/kg os (95% confidence)                                        Coughing stimulus                                                                      Ac. citric                                                                             Capsaicin   2N H.sub.2 SO.sub.4                             ______________________________________                                        Levodropropyzina                                                                         151 (126-180)                                                                            145 (84-252)                                                                              265 (168-240)                               Codein     65 (57-74) 74 (52)107) 102 (55-190)                                Ondasetron 209 (126-349)                                                                            97 (36-261) --                                          Compound A 57 (41-80.5)                                                                             51 (33-77)  --                                          ______________________________________                                         -- not tested                                                            

In both pharmacological tests only7-azaindolyl-3-carboxy-endo-N-tropylamide (Compound A) showed to beeffective. Compound A proved to be at least equiactive as codeine, andadvantageously in respect to the latter, it does not show any increaseof the sleeping time induced by barbiturates.

It is assumed that Capsaicine releases substance P from the peripheralnerve endings of the sensitive fibers C and determines the necrosis ofthe same. It is known that capsaicine administration provokes theformation of an exudate (extra vasation by capsaicine) which can beevaluated by concomitant Evans bleu administration.

Solely Compound A and not Ondasetron has been found to give a 42%protection (in comparison with non-treated animals) from capsaicineextravasation when the compounds are administered at 10 mg/kg dosage byintraperitoneal route. A similar protection has been observed aftercis-2-benzhydryl-1-azabicyclo- 2.2.2!octane-3-(2-methoxybenzyl amine (CP96 345, a non-peptide antagonist of substance P) administration at 10mg/kg i.p. It is worth to underline that the same substance CP 96 345has been found to protect guinea pigs from cough induced by capsaicinbeing a 26 and 42% short cough inhibition evaluated afterintraperitoneal administration of 10 and 40 mg/kg respectively.

Further compound A (N-endo-8-methyl-8-azabicyclo 3,2,1!oct-3-yl)-7-azaindolyl-3-carboxamide has been tested for its antitussiveeffect in comparison to the closest compound belonging to the class ofcompounds of Japanese Kokai Tokkyo Koho JP 04 21 681, i.e.,8-methyl-8-azabicyclo 3,2,1!oct-3-yl)-1-methyl-7-azaindolyl-3-carboxamide. The compounds wereadministered by os at a single dose of 100 mg/kg on mice using asirritant agent capsaicine aqueous solution according to the previousmentioned technique.

                  TABLE V                                                         ______________________________________                                        Compound n° short coughs                                                                     average n° ± s.e.                                                               inhib. %                                    ______________________________________                                        Control  8 6 5 8 7 9  7.2 ± 0.6                                                                              --                                          7-azaindol-                                                                            3 3 0 1 3 1  1.8 ± 0.5                                                                              75%                                         ylcarboxy                                                                     tropylamide                                                                   1-methyl 7-aza-                                                                        9 5 8 8 6 5  6.5 ± 0.7                                                                               6%                                         indolylcarboxy                                                                tropylamide                                                                   ______________________________________                                    

From the data listed in table V, it is evident compound A is effectiveas an antitussive compound; while the corresponding methyl derivativesdisclosed in JP 04 21 681 were practically ineffective.

Further compound A (N-endo-8-methyl-8-azabicyclo |3,2,1|oct-3-yl)-7-azaindolyl-3-carboxamide has been tested for its antitussiveffect in comparison to the closest compound belonging to the class ofcompounds of Jpn. Kokai Tokkyo Koho JP 04 21 681, i.e.8-methyl-8-azabicliclo |3,2,1|oct-3-yl)-1-methyl-7-azaindolyl-3-carboxamide. The compounds wereadministered by os at a single dose of 100 mg/kg on mice using asirritant agent capsaicine aqueous solution according to the previousmentioned technique.

                  TABLE V                                                         ______________________________________                                        Compound n° short coughs                                                                     average n° ± s.e.                                                               inhib. %                                    ______________________________________                                        Control  8 6 5 8 7 9  7.2 ± 0.6                                                                              --                                          7-azaindol-                                                                            3 3 0 1 3 1  1.8 ± 0.5                                                                              75%                                         ylcarboxy                                                                     tropylamide                                                                   1-methyl 7-aza-                                                                        9 5 8 8 6 5  6.5 ± 0.7                                                                               6%                                         indolylcarboxy                                                                tropylamide                                                                   ______________________________________                                    

From the data listed in table V it is evident the effectiveness ofcompound A as antitussive compound while the corresponding methylderivatives disclosed in JP 04 21 681 showed practically to beineffective.

The compounds of the invention can be then therapeutically employed asantitussive agents without the limitation of the opiate ligandantitussive drugs like as codeine. They are useful in the treatment ofcoughs of different origin particularly against tussive manifestationsmediated by substance P.

More particularly the compounds of the present invention are helpful toprevent nocturnal cough stimuli, due to the administration ofACE-inhibitors, widely used in the hypertension treatments of whichconditions the nocturnal cough represents a side effect which is hard tocure.

The compounds of the invention are also useful in the treatment ofinflammatory conditions and more generally of those pathologicalconditions in which substance P and other neuropeptides have aconclusive etiological part and moreover in asthmatic conditions andpain of neurological origin.

The compounds of the invention may be administered by oral, sublingual,endovenous, subcutaneous, intramuscular, rectal route and by inhalation.The preferred doses vary from about 0.05 to about 15 mg/kg/die,depending on the conditions, weight, age of the patient and on theadministration route. Higher dosages of the compounds of the invention,even for a prolonged period of time, have no contraindication because oftheir very low toxicity. Compound A LD₅₀ in mice is 1 g/kg by oralroute.

The compounds of the invention may be therapeutically used in most ofthe pharmaceutical preparations, using conventional techniques andexcipients as are described in "Remington's Pharmaceutical SciencesHandbook" Hack Publ. Co. New York, USA.

These compositions include capsules, tablets, drinkable solutions,suppositories, vials for parenteral route and by inhalation, systemswith controlled release and similar.

We claim:
 1. Tropyl 7-azaindol-3-ylcarboxyamide compound of the formula##STR6## wherein the symbol indicates that the compounds may have an exoor an endo configuration; and R represents hydrogen, a saturated linearor branched C₁ -C₄ alkyl, C₇ -C₉ arylalkyl or (CH₂)n--(C₃ -C₇)cycloalkyl group wherein n is an number between 0 and 4, or a C₁ -C₁₂acyl group;or non-toxic pharmaceutically acceptable acid addition saltsthereof.
 2. A compound according to claim 1, which isN-(endo-8-methyl-8-azabicyclo3.2.1!oct-3-yl)-7-azaindolyl-3-carboxamide.
 3. An antitussivecomposition comprising a therapeutically effective quantity of acompound according to claim 1 or 2 in combination with apharmaceutically acceptable carrier.
 4. An anti-asthmatic compositioncomprising a therapeutically effective quantity of a compound accordingto claim 1 or 2 in combination with a pharmaceutically acceptablecarrier.
 5. An anti-neurological-origin algesia composition comprising atherapeutically effective quantity of a compound according to claim 1 or2 in combination with a pharmaceutically acceptable carrier.